Erythromycin is a broad spectrum macrolide antibiotic produced by a strain of Streptomyces erythreus. This drug has found wide usage in the mitigation and treatment of upper and lower respiratory tract, skin and soft tissue infections of mild to moderate severity. However, oral administration of the drug suffers from a major disadvantage, i.e., erythromycin is unstable in the acid medium found in the stomach. This instability results in erratic absorption of the drug because of changing gastric conditions which cause degradation of the drug to varying degrees depending on such factors as food intake, water volume, activity and emotional stress. As a result of these biological variations, the bioavailability of erythromycin can vary from as little as 20% to 50% absorption, even in the same patient. Generally, less than half the drug ingested is absorbed and available for antimicrobial activity.
Numerous attempts have been made in the past to overcome the problem of gastric degradation and enhance activity by modifying the erythromycin molecule or by modifying the dosage form of the drug. Thus, one approach has been to protect the erythromycin molecule by altering its physical-chemical characteristics, primarily by the preparation of insoluble derivatives such as erythromycin estolate, erythromycin cetyl sulfate, erythromycin propionate, erythromycin stearate and others. The rationale behind this approach has been that an insoluble derivative would be expected to traverse the stomach without significant degradation and then be available for absorption in the alkaline portion of the intestines. Although this approach has shown moderate success, the problem of instability has not been solved and serious bioavailability deficiencies remain.
The other prior art approach to the gastric degradation problem has involved protecting the drug from gastric fluids by preparing tablets of erythromycin which are treated in such a manner as to render them insoluble in the gastric fluids but subject to dissolution in the upper intestinal tract. Thus, a number of firms have prepared and marketed enteric-coated forms of erythromycin base, e.g., Upjohn's E-MYCIN.RTM. tablets. The problem of acid instability has clearly been overcome by this approach, but, again, bioavailability problems remain.
It has been determined that the major approaches employed in the past have not been entirely satisfactory because the insoluble derivatives (e.g., the estolate and cetyl sulfate) and erythromycin base itself are in fact highly insoluble. Thus, these compounds, do not exhibit a high rate of dissolution and in fact dissolve only very slowly as the drug passes down the intestinal tract. This in itself would not be a problem except for the fact that it has been found that erythromycin is absorbed primarily from the duodenum (the first and shortest part of the small intestine, generally being about 10 inches in length), with little or no absorption occurring below this segment of the intestine.